My career goal is to be an academic physician-scientist, performing research at the interface of molecular neuroscience and clinical psychiatry. To achieve this career goal, I trained in Vanderbilts NIH- supported Medical Scientist Training Program and received M.D. and Ph.D. degrees. For my Ph.D. in Microbiology and Immunology in the laboratory of Terence Dermody, M.D., I studied viral pathogenesis of the neurotropic pathogen reovirus, focusing on viral entry and endocytic proteases. I discovered new mechanisms by which endocytic proteases can be regulated, discovered that specific cellular endocytic proteases can determine host susceptibility to infection by an intracellular pathogen, and discovered mechanisms by which non-enveloped viruses disassemble during entry into cells. Though I was excited about new research in virology, I was drawn to the frontiers of neuroscience and the clinical discipline of psychiatry. My clinical training experience in the Massachusetts General Hospital and McLean Hospital Adult Psychiatry Residency Program was superb and rigorous. Currently, I am a Clinical Assistant in Psychiatry at Massachusetts General Hospital, Harvard Medical School where I work one-quarter of weekends and holidays on the Psychiatric Consultation Service under the leadership of Theodore Stern, M.D. This limited clinical work allows me to continue to develop as a clinician and psychiatrist. I am now Board Certified in Psychiatry by the American College of Psychiatry and Neurology. As a physician-scientist in psychiatry, I intend to investigate molecular mechanisms underlying neuropsychiatric disorders. A major impediment to developing new treatments for psychiatric disorders is a lack of understanding of the molecular mechanisms that lead to these disorders. Psychiatric neuroscience is at the beginning of a revolution in which genes are being rigorously linked to these disorders. A major challenge for psychiatry will be to determine how proteins encoded by genes linked to neuropsychiatric disorders function in neurons and the brain. The laboratory of Michael Greenberg, Ph.D. has excelled at identifying molecular mechanisms of neuronal activity-regulated gene expression, synaptic development, and signaling pathways, processes that contribute substantially to neuropsychiatric disorders. A post-doctoral fellowship with Dr. Greenberg provides an optimal training experience for me to develop proficiency in investigating molecular mechanisms of gene expression and synaptic development relevant to psychiatry. Dr. Greenberg, in large part due to his careful mentoring, has an exceptional track record of launching many prominent independent investigators who have become leaders in the field. The environment at Harvard Medical School and Longwood Medical Area provides a rich community and resource in which to train. Following my post-doctoral fellowship in Dr. Greenbergs laboratory, I intend to continue my physician-scientist journey as an independent principal investigator, leading a molecular neuroscience laboratory in an academic medical center, as well as maintaining a limited clinical presence. For my postdoctoral fellowship and the proposed career development award, I am investigating the activity-dependent phosphorylation of MeCP2. Mutations in MeCP2 cause many cases of Rett syndrome and other neuropsychiatric disorders. The mechanisms by which MeCP2 regulates gene expression and synaptic development in the brain remain unclear. Activity-dependent phosphorylation of MeCP2 is one mechanism that modifies its function. Serine 421 was previously identified as a site of activity-dependent phosphorylation that regulates activity-induced Bdnf expression, spine maturation, and dendritic arborization. However, the full complexity of MeCP2 phosphorylation remains a critical gap in knowledge. This grant proposes to identify and characterize additional sites of activity-dependent phosphorylation of MeCP2. In addition, this grant proposes to determine the role of activity-dependent phosphorylation of MeCP2 in Bdnf expression and development of functional inhibitory and excitatory synapses. We anticipate that the proposed experiments will provide a better understanding of mechanisms by which MeCP2 regulates gene expression and synaptic development, and how dysfunction of MeCP2 leads to autism spectrum disorders and other neuropsychiatric phenotypes. Improved understanding of mechanisms of MeCP2 function will hopefully guide development of novel treatments for these disorders. The proposed experiments and career development award will provide a solid foundation for my transition to independence, including generating preliminary date for a R01 as well as opening up multiple new avenues for investigation. In addition, once I have transitioned to independence, using similar techniques to study activity-dependent phosphorylation, gene expression, and synaptic development for other genes and proteins genetically linked to psychiatric disorders will be a powerful and productive approach to further understanding of the molecular mechanisms underlying neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Dysfunction of MeCP2 can lead to Rett syndrome and a subset of autism spectrum disorders and other neuropsychiatric disorders, yet mechanisms by which MeCP2 functions in the brain remain unclear. This grant will investigate how MeCP2 is phosphorylated with neuronal activity and how these phosphorylation events modify MeCP2s regulation of gene expression and synaptic development in the brain. Improved understanding of the mechanism of MeCP2 function may guide the development of new treatments for these disorders in the future.